Composition and method for treating neurological disease

ABSTRACT

Disclosed are compositions comprising amantadine, or a pharmaceutically acceptable salt thereof, and one or more excipients, wherein at least one of the excipients modifies release of amantadine. Methods of administering the same are also provided.

RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/865,830, which is a continuation of U.S. patent application Ser. No.14/591,662, filed Jan. 7, 2015, now abandoned, which is a continuationof U.S. patent application Ser. No. 14/451,262, filed Aug. 4, 2014, nowU.S. Pat. No. 8,987,333, which is a continuation of U.S. patentapplication Ser. No. 14/328,440, filed Jul. 10, 2014, now U.S. Pat. No.8,895,614, which is a continuation of U.S. patent application Ser. No.13/958,153, filed Aug. 2, 2013, now U.S. Pat. No. 8,796,337, which is acontinuation of U.S. patent application Ser. No. 13/756,275, filed Jan.31, 2013, now abandoned, which is a continuation application of U.S.patent application Ser. No. 11/286,448, filed on Nov. 23, 2005, now U.S.Pat. No. 8,389,578, which claims priority to U.S. ProvisionalApplication No. 60/631,095 filed on Nov. 24, 2004, all of whichapplications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to compositions and methods for treatingneurological diseases, such as Parkinson's disease.

BACKGROUND OF THE INVENTION

Parkinson's disease (PD) is a progressive, degenerative neurologicdisorder which usually occurs in late mid-life. PD is clinicallycharacterized by bradykinesia, tremor, and rigidity. Bradykinesia ischaracterized by a slowness in movement, slowing the pace of suchroutine activities as walking and eating. Tremor is a shakiness thatgenerally affects limbs that are not otherwise in motion. For thosePD-patients diagnosed at a relatively young age, tremor is reported asthe most disabling symptom. Older patients face their greatest challengein walking or keeping their balance. Rigidity is caused by the inabilityof muscles to relax as opposing muscle groups contract, causing tensionwhich can produce aches and pains in the back, neck, shoulders, temples,or chest.

PD predominantly affects the substantia nigra (SNc) dopamine (DA)neurons and is therefore associated with a decrease in striatal DAcontent. Because dopamine does not cross the blood-brain barrier, PDpatients may be administered a precursor, levodopa, that does cross theblood-brain barrier where it is metabolized to dopamine. Levodopatherapy is intended to compensate for reduced dopamine levels and is awidely prescribed therapeutic agent for patients with Parkinson'sdisease. Chronic treatment with levodopa however, is associated withvarious debilitating side-effects such as dyskinesia.

Since currently available drugs containing levodopa are associated withdebilitating side effects, better therapies are needed for themanagement of PD.

SUMMARY OF THE INVENTION

In general, the present invention provides methods and compositions fortreating and preventing CNS-related conditions, such as Parkinson'sdisease or other Parkinson's-like diseases or conditions, byadministering to a subject in need thereof a combination that includesan N-Methyl-D-Aspartate receptor (NMDAr) antagonist and levodopa.Exemplary NMDAr antagonists include the aminoadamantanes, such asmemantine (1-amino-3,5- dimethyladamantane), rimantadine(1-(1-aminoethyl)adamantane), or amantadine (1-amino-adamantane) as wellas others described below. Because levodopa is metabolized beforecrossing the blood-brain barrier and has a short half-life in thecirculatory system, it is typically administered in conjunction with adopa-decarboxylase inhibitor. Examples of dopa-decarboxylase inhibitorsinclude carbidopa, 3-hydroxy-benzylhydrazinedihydrochloride (NSD-1015),and benseraxide hydrochloride. The combination may further include acatechol-0- methyltransferase (COMT) inhibitor including, for example,talcapone and entacapone. As used herein, levodopa/carbidopa shall meanlevodopa alone or in combination with a dopa-decarboxylase inhibitorsuch as carbidopa. Desirably, the levodopa/carbidopa is in an immediaterelease formulation and the NMDA receptor antagonist is in an extendedrelease formulation. One preferred embodiment of the invention involvesthe combination of amantadine and levodopa/carbidopa. Desirably,amantadine is provided in an extended release formulation andlevodopa/carbidopa is provided as an immediate release formulation. Bycombining an NMDAr antagonist (e.g., amantadine) with the second agentsdescribed herein (e.g., levodopa/carbidopa), this invention provides aneffective pharmaceutical composition for treating neurological diseasessuch as Parkinson's disease or other Parkinson's-like diseases orconditions. The administration of this combination is postulated tomaintain or enhance the efficacy of levodopa while significantlyreducing its dyskinesia side effects.

The combinations described herein provide complementary benefitsassociated with the NMDAr antagonist or levodopa/carbidopa individually,while minimizing difficulties previously presented when each componentis used separately in a patient. For example, amantadine dosing islimited by neurotoxicity that is likely associated with its short Tmax.By extending the release of amantadine, a higher effective dose can bemaintained providing both dyskinesia relief and a reduction in theamount of levodopa required for treatment of the disease symptoms. Giventhe inherent toxicity of levodopa, such a levodopa sparing combinationwill result in a decline in both the dyskinesia and overall disease.

Accordingly, the pharmaceutical compositions described herein areadministered so as to deliver to a subject, an amount of an NMDArantagonist, levodopa/carbidopa or both agents that is high enough totreat symptoms or damaging effects of an underlying disease whileavoiding undesirable side effects. These compositions may be employed toadminister the NMDAr antagonist, the levodopa/carbidopa, or both agentsat a lower frequency than presently employed, improving patientcompliance, adherence, and caregiver convenience. These compositions areparticularly useful as they provide the NMDAr antagonist,levodopa/carbidopa, or both agents, at a therapeutically effectiveamount from the onset of therapy further improving patient complianceand adherence and enable the achievement of a therapeutically effectivesteady-state concentration of either or both agents of the combinationin a shorter period of time resulting in an earlier indication ofeffectiveness and increasing the utility of these therapeutic agents fordiseases and conditions where time is of the essence. Also provided aremethods for making and using such compositions.

The NMDAr antagonist, the levodopa/carbidopa, or both agents may beprovided in a controlled or extended release form with or without animmediate release component in order to maximize the therapeutic benefitof such agents, while reducing unwanted side effects. In preferredembodiments for oral administration, levodopa/carbidopa is provided asan immediate-release formulation.

The NMDAr antagonist, the levodopa/carbidopa, or both agents may beadministered in an amount similar to that typically administered tosubjects. Preferably, the amount of the NMDAr antagonist may beadministered in an amount greater than or less than the amount that istypically administered to subjects while the levodopa/carbidopa isprovided at a lower dose than normally used. For example, the amount ofamantadine required to positively affect the patient response (inclusiveof adverse effects) may be 300, 400, 500, 600 mg per day rather than thetypical 200 -300 mg per day administered for presently approvedindications i.e. without the improved formulation described herein,while the levodopa, and optionally the carbidopa, can be reducedindependently by 10%, 20%, 30%, 40%, 50%, 60%, 70% or up to 80% of whatis currently required in the absence of the NMDAr antagonist.

Optionally, lower or reduced amounts of both the NMDAr antagonist andthe levodopa/carbidopa are used in a unit dose relative to the amount ofeach agent when administered independently. The present inventiontherefore features formulations of combinations directed to doseoptimization or release modification to reduce adverse effectsassociated with separate administration of each agent. The combinationof the NMDAr antagonist and the levodopa/carbidopa may result in anadditive or synergistic response, and using the unique formulationsdescribed herein, the goal of minimizing the levodopa burden isachieved. Preferably, the NMDAr antagonist and the levodopa/carbidopaare provided in a unit dosage form.

The compositions and methods of the invention are particularly usefulfor the treatment of Parkinson's disease or conditions associated withParkinson's disease. These conditions include dementia, dyskinesia,dystonia, depression, fatigue and other neuropsychiatric complicationsof Parkinson's disease.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the invention, suitable methods and materials aredescribed below. All publications, patent applications, patents, andother references mentioned herein are incorporated by reference in theirentirety. In the case of conflict, the present Specification, includingdefinitions, will control. In addition, the materials, methods, andexamples are illustrative only and not intended to be limiting. Allparts and percentages are by weight unless otherwise specified.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the dissolution profiles for an immediate andsustained release formulation of amantadine. The sustained releaseformulation exhibits a dC/dT during the initial phase that is about 10%of that for the immediate release formulation.

FIG. 2 is a graph showing the amantadine plasma concentration over aperiod of 5 days, as predicted by Gastro-Plus software package v.4.0.2,following the administration of either 70 mg amantadine in an immediaterelease formulation t.i.d. or 75 mg amantadine in a sustained releaseformulation t.i.d. The sustained release formulation peaks are similarin height to the immediate release formulation even with a higheradministered dose and the diurnal variation is substantially reduced.

FIG. 3 is a graph showing the plasma profiles simulated usingGastro-Plus for t.i.d. administration of amantadine (70 mg), levodopa(100 mg), and carbidopa (25 mg), all in an immediate release form.

FIG. 4 is a graph showing the plasma profiles simulated usingGastro-Plus for t.i.d. administration of amantadine (75 mg), levodopa(100 mg), and carbidopa (25 mg), where the amantadine is in a sustainedrelease form and the levodopa and carbidopa are in an immediate releaseform.

FIG. 5 is a graph representing dissolution profiles for variousaminoadamantane formulations including an immediate release form of theNMDAr antagonist memantine (Namenda).

FIG. 6 is a graphical representation of plasma release profiles in ahuman of memantine, levodopa, and carbidopa when memantine isadministered separately from levodopa and carbidopa.

FIG. 7 is a graphical representation of plasma release profiles in ahuman of memantine, levodopa, and carbidopa when memantine, levodopa,and carbidopa are administered as part of a single controlled-releasepharmaceutical composition.

FIG. 8 is a bar graph showing the effects on a primate (squirrel monkey)treated with a combination of levodopa/carbidopa and amantadine.

DETAILED DESCRIPTION OF THE INVENTION

In general, the present invention features pharmaceutical compositionsthat contain therapeutically effective levels of an NMDAr antagonist andlevodopa/carbidopa and, optionally, a pharmaceutical carrier. Preferablythe compositions are formulated for modified or extended release toprovide a serum or plasma concentration of the NMDAr antagonist over adesired time period that is high enough to be therapeutically effectivebut at a rate low enough so as to avoid adverse events associated withthe NMDAr antagonist. Control of drug release is particularly desirablefor reducing and delaying the peak plasma level while maintaining theextent of drug bioavailability. Therapeutic levels are thereforeachieved while minimizing debilitating side-effects that are usuallyassociated with immediate release formulations. Furthermore, as a resultof the delay in the time to obtain peak serum or plasma level and theextended period of time at the therapeutically effective serum or plasmalevel, the dosage frequency is reduced to, for example, once or twicedaily dosage, thereby improving patient compliance and adherence. Forexample, side effects including psychosis and cognitive deficitsassociated with the administration of NMDAr antagonists may be lessenedin severity and frequency through the use of controlled-release methodsthat shift the Tmax to longer times, thereby reducing the dC/dT of thedrug. Reducing the dC/dT of the drug not only increases Tmax, but alsoreduces the drug concentration at Tmax and reduces the Cmax/Cmean ratioproviding a more constant amount of drug to the subject being treatedover a given period of time, enabling increased dosages for appropriateindications.

In addition, the present invention encompasses optimal ratios of NMDArand levodopa/carbidopa, designed to not only treat the dyskinesiaassociated with levodopa, but also take advantage of the additivity andsynergy between these drug classes. For example, the level of levodoparequired to treat the disease symptoms can unexpectedly be reduced by upto 50% by the addition of 400 mg/day of amantadine.

Making NMDAr Antagonist Controlled Release Formulations

A pharmaceutical composition according to the invention is prepared bycombining a desired NMDAr antagonist or antagonists with one or moreadditional ingredients that, when administered to a subject, causes theNMDAr antagonist to be released at a targeted rate for a specifiedperiod of time. A release profile, i.e., the extent of release of theNMDAr antagonist over a desired time, can be conveniently determined fora given time by measuring the release using a USP dissolution apparatusunder controlled conditions. Preferred release profiles are those whichslow the rate of uptake of the NMDAr antagonist in the neural fluidswhile providing therapeutically effective levels of the NMDArantagonist. One of ordinary skill in the art can prepare combinationswith a desired release profile using the NMDAr antagonists andformulation methods described below.

NMDAr Antagonists

Any NMDAr antagonist can be used in the methods and compositions of theinvention, particularly those that are non-toxic when used in thecompositions of the invention. The term “nontoxic” is used in a relativesense and is intended to designate any substance that has been approvedby the United States Food and Drug Administration (“FDA”) foradministration to humans or, in keeping with established regulatorycriteria and practice, is susceptible to approval by the FDA or similarregulatory agency for any country for administration to humans oranimals.

The term “NMDAr antagonist”, as used herein, includes anyamino-adamantane compound including, for example, memantine(1-amino-3,5-dimethyladamantane), rimantadine(1-(1-aminoethyl)adamantane), amantadine (1-amino-adamantane), as wellas pharmaceutically acceptable salts thereof. Memantine is described,for example, in U.S. Pat. Nos. 3,391,142, 5,891,885, 5,919,826, and6,187,338. Amantadine is described, for example, in U.S. Pat. Nos.3,152,180, 5,891,885, 5,919,826, and 6,187,338. Additionalaminoadamantane compounds are described, for example, in U.S. Pat. Nos.4,346,112, 5,061,703, 5,334,618, 6,444,702, 6,620,845, and 6,662,845.All of these patents are hereby incorporated by reference.

Further NMDAr antagonists that may be employed include, for example,aminocylohexanes such as neramexane, ketamine, eliprodil, ifenprodil,dizocilpine, remacemide, iamotrigine, riluzole, aptiganel,phencyclidine, flupirtine, celfotel, felbamate, spermine, spermidine,levemopamil, dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) and itsmetabolite, dextrorphan ((+)-3-hydroxy-N-methylmorphinan), apharmaceutically acceptable salt, derivative, or ester thereof, or ametabolic precursor of any of the foregoing.

Optionally, the NMDAr antagonist in the instant invention is memantineand not amantadine or dextromethorphan.

Second Agents

In all foregoing aspects of the invention, the second agent is levodopa.When levodopa is in the combination, the combination preferably alsoincludes a dopa-decarboxylase inhibitor. An example of a suitabledopa-decarboxylase inhibitor is carbidopa. Other dopa-decarboxylaseinhibitors include, for example,3-hydroxy-benzylhydrazinedihydrochloride (NSD-1015) and benseraxidehydrochloride. The combination may further include acatechol-O-methyltransferase (COMT) inhibitor including, for example,talcapone and entacapone.

Dosing, PK, & Toxicity

The NMDA receptor antagonist used in combination therapies areadministered at a dosage of generally between about 1 and 5000 mg/day,between 1 and about 800mg/day, or between 1 and 500 mg/day. For example,NMDA receptor antagonist agents may be administered at a dosage rangingbetween about 1 and about 500mg/day, more preferably from about 10 toabout 40, 50, 60, 70 or 80 mg/day, advantageously from about 10 to about20 mg per day. Amantadine may be administered at a dose ranging fromabout 90, 100 mg/day to about 400, 500, 600, 700 or 800 mg/day,advantageously from about 100 to about 500, 600 mg per day. For example,the pharmaceutical composition may be formulated to provide memantine inan amount ranging between 1-200 mg/day, 1 and 80 mg/day, 2-80 mg/day,10-80 mg/day, 10 and 80 mg/day, 10 and 70 mg/day, 10 and 60 mg/day, 10and 50 mg/day, 10 and 40 mg/day, 5 and 65 mg/day, 5 and 40 mg/day, 15and 45 mg/day, or 10 and 20 mg/day; dextromethorphan in an amountranging between 1-5000 mg/day, 1-1000 mg/day, and 100-800 mg/day, or200-500 mg/day. Pediatric doses will typically be lower than thosedetermined for adults.

Table 1 shows exemplary pharmacokinetic properties (e.g., Tmax and T1/2)of memantine, amantadine, and rimantadine.

TABLE 1 Pharmacokinetics and Toxicity in humans for selected NIVIDArantagonists Human PK Dose (t 1/2) Tmax Dependent Compound (hours)(hours) Normal Dose Toxicity Memantine 60 3 10-20 mg/day, Doseescalation starting at 5 mg required, hallucination Amantadine 15 3100-300 mg/day, Hallucination starting at 100 mg/day Rimantadine 25 6100-200 mg/day Insomnia

When levodopa and carbidopa are both included in the composition, thelevodopa dose ranges between 100 to 3000 mg per day, 75 mg and 2500mg/day, 100-2000 mg/day, or 250 and 1000 mg/day divided foradministration t.i.d. or more frequently. Carbidopa doses may rangebetween the amounts of 1 to 1000 mg/day, 10 to 500 mg/day, and 25 to100mg/day. Optionally, the carbidopa is present in the combination atabout 75%, 70%, 65%, 60%, 50%, 40%, 30%, 25%, 20%, and 10% of the massof the levodopa. Alternatively, the amount of levodopa is less than 300%than the amount of carbidopa. For example, 75 mg of carbidopa (amountthat is sufficient to extend the half-life of levodopa in thecirculatory system) may be used in combination with 300 to 3000 mg oflevodopa per day. The combination may contain a single dosage formcomprising 30 to 200 mg amantadine, 30 to 250 mg levodopa, and 10 to 100mg of carbidopa for t.i.d. or more frequent administration, includingmultiple dosage forms per administration.

As a result, the preferred dosage forms for optimized use are shown inTable 2 below, with their corresponding commercial equivalent.

TABLE 2 Dosage forms with and without NMDAr antagonist (amount per unitdose) Sinemet Compositions Compositions of Present Invention LevodopaCarbidopa Levodopa Carbidopa Amantadine 100 mg 25 mg IR 50-100 mg 25 mgIR 100-200 mg  IR* IR IR 100 mg 10 mg IR 50-100 mg 10 mg IR  50-100 mgIR IR IR 100 mg 25 mg IR 50-100 mg 25 mg IR 100-200 mg IR IR  CR** 100mg 10 mg IR 50-100 mg 10 mg IR  50-100 mg IR IR CR *IR: immediaterelease **CR: modified release

Excipients

“Pharmaceutically or Pharmacologically Acceptable” includes molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. “Pharmaceutically Acceptable Carrier” includes any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutical active substances is well knownin the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions. “Pharmaceutically AcceptableSalts” include acid addition salts and which are formed with inorganicacids such as, for example, hydrochloric or phosphoric acids, or suchorganic acids as acetic, oxalic, tartaric, mandelic, and the like. Saltsformed with the free carboxyl groups can also be derived from inorganicbases such as, for example, sodium, potassium, ammonium, calcium, orferric hydroxides, and such organic bases as isopropylamine,trimethylamine, histidine, procaine and the like.

The preparation of pharmaceutical or pharmacological compositions isknown to those of skill in the art in light of the present disclosure.General techniques for formulation and administration are found in“Remington: The Science and Practice of Pharmacy, Twentieth Edition,”Lippincott Williams & Wilkins, Philadelphia, Pa. Tablets, capsules,pills, powders, granules, dragees, gels, slurries, ointments, solutionssuppositories, injections, inhalants and aerosols are examples of suchformulations.

By way of example, modified or extended release oral formulation can beprepared using additional methods known in the art. For example, asuitable extended release form of the either active pharmaceuticalingredient or both may be a matrix tablet or capsule composition.Suitable matrix forming materials include, for example, waxes (e.g.,carnauba, bees wax, paraffin wax, ceresine, shellac wax, fatty acids,and fatty alcohols), oils, hardened oils or fats (e.g., hardenedrapeseed oil, castor oil, beef tallow, palm oil, and soya bean oil), andpolymers (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone,hydroxypropyl methyl cellulose, and polyethylene glycol). Other suitablematrix tabletting materials are microcrystalline cellulose, powderedcellulose, hydroxypropyl cellulose, ethyl cellulose, with othercarriers, and fillers. Tablets may also contain granulates, coatedpowders, or pellets. Tablets may also be multi-layered. Multi-layeredtablets are especially preferred when the active ingredients havemarkedly different pharmacokinetic profiles. Optionally, the finishedtablet may be coated or uncoated.

The coating composition typically contains an insoluble matrix polymer(approximately 15-85% by weight of the coating composition) and a watersoluble material (e.g., approximately 15-85% by weight of the coatingcomposition). Optionally an enteric polymer (approximately 1 to 99% byweight of the coating composition) may be used or included. Suitablewater soluble materials include polymers such as polyethylene glycol,hydroxypropyl cellulose, hydroxypropyl methyl cellulose,polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials such assugars (e.g., lactose, sucrose, fructose, mannitol and the like), salts(e.g., sodium chloride, potassium chloride and the like), organic acids(e.g., fumaric acid, succinic acid, lactic acid, and tartaric acid), andmixtures thereof. Suitable enteric polymers include hydroxypropyl methylcellulose, acetate succinate, hydroxypropyl methyl cellulose, phthalate,polyvinyl acetate phthalate, cellulose acetate phthalate, celluloseacetate trimellitate, shellac, zein, and polymethacrylates containingcarboxyl groups.

The coating composition may be plasticised according to the propertiesof the coating blend such as the glass transition temperature of themain component or mixture of components or the solvent used for applyingthe coating compositions. Suitable plasticisers may be added from 0 to50% by weight of the coating composition and include, for example,diethyl phthalate, citrate esters, polyethylene glycol, glycerol,acetylated glycerides, acetylated citrate esters, dibutylsebacate, andcastor oil. If desired, the coating composition may include a filler.The amount of the filler may be I % to approximately 99% by weight basedon the total weight of the coating composition and may be an insolublematerial such as silicon dioxide, titanium dioxide, talc, kaolin,alumina, starch, powdered cellulose, MCC, or polacrilin potassium.

The coating composition may be applied as a solution or latex in organicsolvents or aqueous solvents or mixtures thereof. If solutions areapplied, the solvent may be present in amounts from approximate by25-99% by weight based on the total weight of dissolved solids. Suitablesolvents are water, lower alcohol, lower chlorinated hydrocarbons,ketones, or mixtures thereof. If latexes are applied, the solvent ispresent in amounts from approximately 25-97% by weight based on thequantity of polymeric material in the latex. The solvent may bepredominantly water.

The NMDAr antagonist may be formulated using any of the followingexcipients or combinations thereof.

Excipient name Chemical name Function Avicel PH102 MicrocrystallineCellulose Filler, binder, wicking, disintegrant Avicel PH101Microcrystalline Cellulose Filler, binder, disintegrant Eudragit RS-Polymethacrylate Poly(ethyl acrylate, Film former, tablet binder, tabletdiluent; 30D nethyl methacrylate, Rate controlling polymer forcontrolled timethylammonioethyl methacrylate release chloride) 1:2:0.1Methocel Hydroxypropyl methylcellulose Rate controlling polymer forcontrolled K100M release; binder; viscosity-increasing Premium CR agentMethocel Hydroxypropyl methylcellulose Rate controlling polymer forcontrolled K100M release; binder; viscosity-increasing agent MagnesiumMagnesium Stearate Lubricant Stearate Talc Talc Dissolution control;anti-adherent, glidant Triethyl Citrate Triethyl Citrate PlasticizerMethocel E5 Hydroxypropyl methylcellulose Film-former Opadry ®Hydroxypropyl methylcellulose One-step customized coating system whichcombines polymer, plasticizer and, if desired, pigment in a dryconcentrate. Surelease ® Aqueous Ethylcellulose Dispersion Film-formingpolymer; plasticizer and stabilizers. Rate controlling polymer coating.

The pharmaceutical composition described herein may also include acarrier such as a solvent, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Pharmaceutically acceptable salts can also be used inthe composition, for example, mineral salts such as hydrochlorides,hydrobromides, phosphates, or sulfates, as well as the salts of organicacids such as acetates, proprionates, malonates, or benzoates. Thecomposition may also contain liquids, such as water, saline, glycerol,and ethanol, as well as substances such as wetting agents, emulsifyingagents, or pH buffering agents. Liposomes, such as those described inU.S. Pat. No. 5,422,120, WO 95/13796, WO 91/14445, or EP 524,968 B1, mayalso be used as a carrier.

Methods for Preparing Modified or Extended Release Formulations

The NMDAr antagonist, the levodopa/carbidopa, or both agents may beprovided in a controlled or extended release form with or without animmediate release component in order to maximize the therapeutic benefitof such agents, while reducing unwanted side effects. In the absence ofmodified release components (referred to herein as controlled, extended,or delayed release components), the NMDAr antagonist,levodopa/carbidopa, or both is released and transported into the bodyfluids over a period of minutes to several hours. The combinationdescribed herein however, may contain an NMDAr antagonist and asustained release component, such as a coated sustained release matrix,a sustained release matrix, or a sustained release bead matrix. In oneexample, in addition to levodopa/carbidopa, amantadine (e.g., 50-1400mg) is formulated without an immediate release component using a polymermatrix (e.g., Eudragit), Hydroxypropyl methyl cellulose (HPMC) and apolymer coating (e.g., Eudragit). Such formulations are compressed intosolid tablets or granules and coated with a controlled release materialsuch as Opadry® or Surelease®. Levodopa/carbidopa may also be formulatedas a sustained release formulation; in most cases, however, this willnot be optimal.

Suitable methods for preparing the compositions described herein inwhich the NMDAr antagonist is provided in modified or extendedrelease-formulations include those described in U.S. Pat. No. 4,606,909(hereby incorporated by reference). This reference describes acontrolled release multiple unit formulation in which a multiplicity ofindividually coated or microencapsulated units are made available upondisintegration of the formulation (e.g., pill or tablet) in the stomachof the subject (see, for example, column 3, line 26 through column 5,line 10 and column 6, line 29 through column 9, line 16). Each of theseindividually coated or microencapsulated units containscross-sectionally substantially homogenous cores containing particles ofa sparingly soluble active substance, the cores being coated with acoating that is substantially resistant to gastric conditions but whichis erodable under the conditions prevailing in the gastrointestinaltract.

The composition of the invention may alternatively be formulated usingthe methods disclosed in U.S. Pat. No. 4,769,027, for example.Accordingly, extended release formulations involve prills ofpharmaceutically acceptable material (e.g., sugar/starch, salts, andwaxes) may be coated with a water permeable polymeric matrix containingan NMDAr antagonist and next overcoated with a water-permeable filmcontaining dispersed within it a water soluble particulate pore formingmaterial.

The NMDAr antagonist composition may additionally be prepared asdescribed in U.S. Pat. No. 4,897,268, involving a biocompatible,biodegradable microcapsule delivery system. Thus, the NMDAr antagonistmay be formulated as a composition containing a blend of free-flowingspherical particles obtained by individually microencapsulatingquantities of memantine, for example, in different copolymer excipientswhich biodegrade at different rates, therefore releasing memantine intothe circulation at a predetermined rates. A quantity of these particlesmay be of such a copolymer excipient that the core active ingredient isreleased quickly after administration, and thereby delivers the activeingredient for an initial period. A second quantity of the particles isof such type excipient that delivery of the encapsulated ingredientbegins as the first quantity's delivery begins to decline. A thirdquantity of ingredient may be encapsulated with a still differentexcipient which results in delivery beginning as the delivery of thesecond quantity beings to decline. The rate of delivery may be altered,for example, by varying the lactide/glycolide ratio in apoly(D,L-lactide-co-glycolide) encapsulation. Other polymers that may beused include polyacetal polymers, polyorthoesters, polyesteramides,polycaprolactone and copolymers thereof, polycarbonates,polyhydroxybuterate and copolymers thereof, polymaleamides,copolyaxalates and polysaccharides.

Alternatively, the composition may be prepared as described in U.S. Pat.No. 5,395,626, which features a multilayered controlled releasepharmaceutical dosage form. The dosage form contains a plurality ofcoated particles wherein each has multiple layers about a corecontaining an NMDAr antagonist whereby the drug containing core and atleast one other layer of drug active is overcoated with a controlledrelease barrier layer therefore providing at least two controlledreleasing layers of a water soluble drug from the multilayered coatedparticle

Release Profile

The compositions described herein are formulated such that the NMDArantagonist, levodopa/carbidopa, or both agents have an in vitrodissolution profile that is equal to or slower than that for animmediate release formulation. As used herein, the immediate release(IR) formulation for memantine means the present commercially available5 mg and 10 mg tablets (i.e., Namenda from Forest Laboratories, Inc. orformulations having substantially the same release profiles as Namenda);and the immediate release (IR) formulation of amantadine means thepresent commercially available 100 mg tablets (i.e., Symmetrel from EndoPharmaceuticals, Inc. or formulations having substantially the samerelease profiles as Symmetrel); and the immediate release (IR)formulation of levodopa/carbidopa means the present commerciallyavailable 25 mg/100mg, 10 mg/100 mg, 25 mg/250 mg tablets ofcarbidopa/levodopa (i.e., Sinemet from Merck & Co. Inc. or formulationshaving substantially the same release profiles as Sinemet). Thesecompositions may comprise immediate release, sustained or extendedrelease, or delayed release components, or may include combinations ofsame to produce release profiles such that the fraction of NMDArantagonist or levodopa/carbidopa released is greater or equal to0.01(0.297+0.0153*e^((0.515*t))) and less than or equal to1−e^((−10.9*t)) as measured using a USP type 2 (paddle) dissolutionsystem at 50 rpm, at a temperature of 37±0.5° C., in water, where t isthe time in hours and t is greater than zero and equal or less than 17.Thus, the fraction of NMDAr antagonist or levodopa/carbidopa released isless than 93% in 15 minutes and 7.7%-100% in 12 hours using a USP type 2(paddle) dissolution system at 50 rpm, at a temperature of 37±0.5° C. ina neutral pH (e.g. water or buffered aqueous solution) or acidic (e.g.0.1 N HCl ) dissolution medium. Optionally, the fraction of releasedNMDAr antagonist or levodopa/carbidopa is greater than or equal to0.01(0.297+0.0153*e^((0.515*t))), and less than or equal to1−e^((−0.972*t)) as measured using a USP type 2 (paddle) dissolutionsystem at 50 rpm, at a temperature of 37±0.5° C., in water, where t isthe time in hours and t is greater than zero and equal or less than 17.Thus, the fraction of NMDAr antagonist or levodopa/carbidopa that isreleased may range between 0.1%-62% in one hour, 0.2%-86% in two hours,0.6%-100% in six hours, 2.9%-100% in 10 hours, and 7.7%-100% in 12 hoursusing a USP type 2 (paddle) dissolution system at 50 rpm, at atemperature of 37±0.5° C. in a neutral pH (e.g. water or bufferedaqueous solution) or acidic (e.g. 0.1 N HCl) dissolution medium.Optionally, the NMDA receptor antagonist has a release profile rangingbetween 0.1%-20% in one hour, 5%-30% in two hours, 40%-80% in six hours,70% or greater (e.g., 70%-90%) in 10 hours, and 90% or greater (e.g.,90-95%) in 12 hours as measured in a dissolution media having a neutralpH (e.g. water or buffered aqueous solution) or in an acidic (e.g. 0.1 NHCl) dissolution medium. For example, a formulation containingamantadine may have a release profile ranging between 0-60% or 0.1-20%in one hour, 0-86% or 5-30% at two hours, 0.6-100% or 40-80% at sixhours, 3-100% or 50% or more (e.g., 50-90%) at ten hours, and 7.7-100%at twelve hours in a dissolution media having a neutral pH (e.g. wateror buffered aqueous solution) or in an acidic (e.g. 0.1 N HCl)dissolution medium. In one embodiment, the NMDAr antagonist, thelevodopa/carbidopa, or both agents have an in vitro dissolution profileof less than 25%, 15%, 10%, or 5% in fifteen minutes; 50%, 30%, 25%,20%, 15%, or 10% in 30 minutes and more than 60%, 65% 70%, 75%, 80%,85%, 90%, 95% at 16 hours as obtained using a USP type II (paddle)dissolution system at 50 rpm, at a temperature of 37±0.5° C. in water.Desirably, the NMDAr antagonist, the levodopa/carbidopa, or both agentshas a dissolution of at least 65%, 70%, 75%, 80%, 85%, 90%, or 95% in adissolution media having a pH of 1.2 at 10 hours. It is important tonote that the dissolution profile for the NMDAr antagonist may bedifferent than the release profile for levodopa/carbidopa. In apreferred embodiment, the levodopa/carbidopa release profile is equal toor similar to that for an immediate release formulation and the releaseprofile for the NMDAr antagonist is controlled to provide a dissolutionprofile of less than 30% in one hour, less than 50% in two hours, andgreater than 95% in twelve hours using a USP type II (paddle)dissolution system at 50 rpm, at a temperature of 37±0.5° C. in water.

Desirably, the compositions described herein have an in vitro profilethat is substantially identical to the dissolution profile shown in FIG.5 and, upon administration to a subject at a substantially constantdaily dose, achieves a serum concentration profile that is substantiallyidentical to that shown in FIGS. 2 and 4.

As described above, the NMDAr antagonist, the levodopa/carbidopa, orboth agents may be provided in a modified or extended release form.Modified or extended drug release is generally controlled either bydiffusion through a coating or matrix or by erosion of a coating ormatrix by a process dependent on, for example, enzymes or pH. The NMDArantagonist or the levodopa/carbidopa may be formulated for modified orextended release as described herein or using standard techniques in theart. In one example, at least 50%, 75%, 90%, 95%, 96%, 97%, 98%, 99%, oreven in excess of 99% of the NMDAr antagonist or the levodopa/carbidopais provided in an extended release dosage form. In a preferredembodiment, the levodopa/carbidopa is provided in an immediate releaseformulation and the NMDAr antagonist is in either an immediate ormodified release form.

The composition described herein is formulated such the NMDAr antagonistor levodopa/carbidopa has an in vitro dissolution profile rangingbetween 0.1%-20% in one hour, 5%-30% in two hours, 40%-80% in six hours,50%-90% in 10 hours, and 90%-95% in 12 hours using a USP type 2 (paddle)dissolution system at 50 rpm, at a temperature of 37±0.5° C. using 0.1NHC1 as a dissolution medium. Alternatively, the NMDAr antagonist has anin vitro dissolution profile in a solution with a neutral pH (e.g.,water) that is substantially the same as its dissolution profile in anacidic dissolution medium. Thus, the NMDAr antagonist may be released inboth dissolution media at the following rate: between 0.1-20% in onehour, 5-30% in two hours, 40-80% in six hours, 70-90% in 10 hours, and90%-95% in 12 hours as obtained using a USP type 2 (paddle) dissolutionsystem at 50 rpm, at a temperature of 37±0.5° C. In one embodiment, theNMDAr antagonist has an in vitro dissolution profile of less than 15%,10%, or 5% in fifteen minutes, 25%, 20%, 15%, or 10% in 30 minutes, andmore than 60% at 16 hours as obtained using a USP type II (paddle)dissolution system at 50 rpm, at a temperature of 37±0.5° C. in water.Desirably, the NMDAr antagonist has a dissolution of at least 65%, 70%,75%, 80%, 85%, 90%, or 95% at 10 hours in a dissolution medium having apH of 1.2.

Initial Rate in Vivo, Delayed Tmax

As used herein, “C” refers to the concentration of an activepharmaceutical ingredient in a biological sample, such as a patientsample (e.g. blood, serum, and cerebrospinal fluid). The time requiredto reach the maximal concentration (“Cmax”) in a particular patientsample type is referred to as the “Tmax”. The change in concentration istermed “dC” and the change over a prescribed time is “dC/dT”.

The NMDAr antagonist or levodopa/carbidopa is provided as a sustainedrelease formulation that may or may not contain an immediate releaseformulation. If desired, the NMDAr antagonist may be formulated so thatit is released at a rate that is significantly reduced over an immediaterelease (IR) dosage form, with an associated delay in the Tmax. Thepharmaceutical composition may be formulated to provide a shift in Tmaxby 24 hours, 16 hours, 8 hours, 4 hours, 2 hours, or at least 1 hour.The associated reduction in dC/dT may be by a factor of approximately0.05, 0.10, 0.25, 0.5 or at least 0.8. In addition, the NMDAr antagonistlevodopa/carbidopa may be provided such that it is released at a rateresulting in a Cmax /Cmean of approximately 2 or less for approximately2 hours to at least 8 hours after the NMDAr antagonist is introducedinto a subject. Optionally, the sustained release formulations exhibitplasma concentration curves having initial (e.g., from 0, 1, 2 hoursafter administration to 4, 6, 8 hours after administration) slopes lessthan 75%, 50%, 40%, 30%, 20% or 10% of those for an IR formulation ofthe same dosage of the same NMDAr antagonist. The precise slope for agiven individual will vary according to the NMDAr antagonist being usedor other factors, including whether the patient has eaten or not. Forother doses, e.g., those mentioned above, the slopes vary directly inrelationship to dose. The determination of initial slopes of plasmaconcentration is described, for example, by U.S. Pat. No. 6,913,768,hereby incorporated by reference.

Desirably, the NMDAr antagonist or the levodopa/carbidopa is releasedinto a subject sample at a slower rate than observed for an immediaterelease (IR) formulation of the same quantity of the antagonist, suchthat the rate of change in the biological sample measured as the dC/dTover a defined period within the period of 0 to Tmax for the IRformulation (e.g., Namenda, a commercially available IR formulation ofmemantine). In some embodiments, the dC/dT rate is less than about 80%,70%, 60%, 50%, 40%, 30%, 20%, or 10% of the rate for the IR formulation.In some embodiments, the dC/dT rate is less than about 60%, 50%, 40%,30%, 20%, or 10% of the rate for the IR formulation. Similarly, the rateof release of the NMDAr antagonist or the levodopa/carbidopa from thepresent invention as measured in dissolution studies is less than 80%,70%, 60% 50%, 40%, 30%, 20%, or 10% of the rate for an IR formulation ofthe same NMDAr antagonist or levodopa/carbidopa over the first 1, 2, 4,6, 8, 10, or 12 hours.

In a preferred embodiment, the dosage form is provided in a non-doseescalating, three times per day (t.i.d.) form. In preferred embodiments,the concentration ramp (or Tmax effect) may be reduced so that thechange in concentration as a function of time (dC/dT) is altered toreduce or eliminate the need to dose escalate the NMDAr antagonist. Areduction in dC/dT may be accomplished, for example, by increasing theTmax in a relatively proportional manner. Accordingly, a two-foldincrease in the Tmax value may reduce dC/dT by approximately a factor of2. Thus, the NMDAr antagonist may be provided so that it is released ata rate that is significantly reduced over an immediate release (IR)dosage form, with an associated delay in the Tmax. The pharmaceuticalcomposition may be formulated to provide a shift in Tmax by 24 hours, 16hours, 8 hours, 4 hours, 2 hours, or at least 1 hour. The associatedreduction in dC/dT may be by a factor of approximately 0.05, 0.10, 0.25,0.5 or at least 0.8. In certain embodiments, this is accomplished byreleasing less than 30%, 50%, 75%, 90%, or 95% of the NMDAr antagonistinto the circulatory or neural system within one hour of suchadministration.

The concentration ramp for levodopa/carbidopa may also be reduced,however such changes will not be preferred in most oral formulations dueto the marked reduction in absorption of levodopa/carbidopa after itpasses the duodenal region of the gastrointestinal tract.

Optionally, the modified release formulations exhibit plasmaconcentration curves having initial (e.g., from-2 hours afteradministration to 4 hours after administration) slopes less-than 75%,50%, 40%, 30%, 20% or 10% of those for an IR formulation of the samedosage of the same NMDAr antagonist or levodopa/carbidopa. The preciseslope for a given individual will vary according to the NMDAr antagonistor levodopa/carbidopa being used, the quantity delivered, or otherfactors, including, for some active pharmaceutical agents, whether thepatient has eaten or not. For other doses, e.g., those mentioned above,the slopes vary directly in relationship to dose.

Using the sustained release formulations or administration methodsdescribed herein, the NMDAr antagonist reaches a therapeuticallyeffective steady state plasma concentration in a subject within thecourse of the first two, three, five, seven, nine, ten, twelve, fifteen,or twenty days of administration. For example, the formulationsdescribed herein, when administered at a substantially constant dailydose (e.g., at a dose ranging between 200 mg and 800 mg, preferablybetween 200 mg and 600 mg, and more preferably between 200 mg and 400 mgper day) may reach a steady state plasma concentration in approximately70%, 60%, 50%, 40%, 30%, or less of the time required to reach suchplasma concentration when using a dose escalating regimen.

Dosing Frequency and Dose Escalation

According to the present invention, a subject (e.g., human) having or atrisk of having such conditions is administered any of the compositionsdescribed herein (e.g., three times per day (t.i.d.), twice per day(b.i.d.), or once per day (q.d.)). While immediate release formulationsof NMDAr antagonists are typically administered in a dose-escalatingfashion, the compositions described herein may be essentiallyadministered at a constant, therapeutically-effective dose from theonset of therapy. For example, a composition containing a sustainedrelease formulation of amantadine may be administered three times perday, twice per day, or once per day in a unit dose comprising a totaldaily amantadine dose of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg,700 mg, or 800mg. In embodiments comprising a single dosage formcontaining an NMDAr antagonist and levodopa/carbidopa wherein thelevodopa/carbidopa is in an immediate release form, the dosing frequencywill be chosen according to the levodopa/carbidopa requirements, (e.g.three times per day).

Reduced Time to Therapeutic Concentration and Efficacy

Immediate release (IR) formulations of memantine (e.g., Namenda) aretypically administered at low doses (e.g., 5 mg/day) and areprogressively administered at increasing frequency and dose over time toreach a steady state serum concentration that is therapeuticallyeffective. According to the manufacturer's FDA approved label, Namenda,an immediate release (IR) formulation of memantine, is firstadministered to subjects at a dose of 5 mg per day. After an acclimationperiod of typically one week, subjects are administered with this dosetwice per day. Subjects are next administered with a 5 mg and 10 mgdosing per day and finally administered with 10 mg Namenda twice daily.Using this dosing regimen, a therapeutically effective steady stateserum concentration may be achieved within 30 days of the onset oftherapy. Using a modified release formulation comprising (22.5 mgmemantine,) however, a therapeutically effective steady stateconcentration may be achieved substantially sooner (within about 13days), without using a dose escalating regimen. Furthermore, the slopeduring each absorption period for the sustained release formulation isless (i.e. not as steep) as the slope for Namenda. Accordingly, thedC/dT of the sustained release formulation is reduced relative to theimmediate release formulation even though the dose administered islarger than for the immediate release formulation. Based on this model,a sustained release formulation of an NMDAr antagonist may beadministered to a subject in an amount that is approximately the fullstrength dose (or that effectively reaches a therapeutically effectivedose) from the onset of therapy and throughout the duration oftreatment. Accordingly, a dose escalation would not be required.

Treatment of a subject with the subject of the present invention may bemonitored using methods known in the art. The efficacy of treatmentusing the composition is preferably evaluated by examining the subject'ssymptoms in a quantitative way, e.g., by noting a decrease in thefrequency or severity of symptoms or damaging effects of the condition,or an increase in the time for sustained worsening of symptoms. In asuccessful treatment, the subject's status will have improved (i.e.,frequency or severity of symptoms or damaging effects will havedecreased, or the time to sustained progression will have increased). Inthe model described in the previous paragraph, the steady state (andeffective) concentration of the NMDAr antagonist is reached in 25%, 40%,50%, 60%, 70%, 75%, or 80% less time than in the dose escalatedapproach.

In another embodiment, a composition is prepared using the methodsdescribed herein, wherein such composition comprises memantine oramantadine and a release modifying excipient, wherein the excipient ispresent in an amount sufficient to ameliorate or reduce thedose-dependent toxicity associated with the memantine or amantadinerelative to an immediate release (IR) formulation of memantine, such asNamenda, or amantadine, such as Symmetrel. The use of these compositionsenables safer administration of these agents, and even permits the safeuse of higher levels for appropriate indications, beyond the usefulrange for the presently available versions of memantine (5 mg and 10 mgper dose to 20 mg per day) and amantadine (100 mg to 300 mg per day withescalation).

Indications Suitable for Treatment

The compositions and methods of the present invention are particularlysuitable for the treatment of Parkinson's disease or conditionsassociated with Parkinson's disease. These conditions include dementia,dyskinesia, dystonia, depression, fatigue and other neuropsychiatriccomplications of Parkinson's disease.

Formulations for Alternate Specific Routes of Administration

The pharmaceutical compositions may be optimized for particular types ofdelivery. For example, pharmaceutical compositions for oral delivery areformulated using pharmaceutically acceptable carriers that are wellknown in the art. The carriers enable the agents in the composition tobe formulated, for example, as a tablet, pill, capsule, solution,suspension, sustained release formulation; powder, liquid or gel fororal ingestion by the subject.

The NMDAr antagonist may also be delivered in an aerosol spraypreparation from a pressurized pack, a nebulizer or from a dry powderinhaler. Suitable propellants that can be used in a nebulizer include,for example, dichlorodifluoro-methane, trichlorofluoromethane,dichlorotetrafluoroethane and carbon dioxide. The dosage can bedetermined by providing a valve to deliver a regulated amount of thecompound in the case of a pressurized aerosol.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral,intranasal or respiratory route for local or systemic effect.Compositions in preferably sterile pharmaceutically acceptable solventsmay be nebulized by use of inert gases. Nebulized solutions may bebreathed directly from the nebulizing device or the nebulizing devicemay be attached to a face mask, tent or intermittent positive pressurebreathing machine. Solution, suspension or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

In some embodiments, for example, the composition may be deliveredintranasally to the cribriform plate rather than by inhalation to enabletransfer of the active agents through the olfactory passages into theCNS and reducing the systemic administration. Devices commonly used forthis route of administration are included in U.S. Pat. No. 6,715,485.Compositions delivered via this route may enable increased CNS dosing orreduced total body burden reducing systemic toxicity risks associatedwith certain drugs.

Additional formulations suitable for other modes of administrationinclude rectal capsules or suppositories. For suppositories, traditionalbinders and carriers may include, for example, polyalkylene glycols ortriglycerides; such suppositories may be formed from mixtures containingthe active ingredient in the range of 0.5% to 10%, preferably 1%-2%.

The composition may optionally be formulated for delivery in a vesselthat provides for continuous long-term delivery, e.g., for delivery upto 30 days, 60 days, 90 days, 180 days, or one year. For example thevessel can be provided in a biocompatible material such as titanium.Long-term delivery formulations are particularly useful in subjects withchronic conditions, for assuring improved patient compliance, and forenhancing the stability of the compositions.

Optionally, the NMDA receptor antagonist, levodopa/carbidopa, or both isprepared using the OROS® technology, described for example, in U.S. Pat.Nos. 6,919,373, 6,923,800, 6,929,803, 6,939,556, and 6,930,128, all ofwhich are hereby incorporated by reference. This technology employsosmosis to provide precise, controlled drug delivery for up to 24 hoursand can be used with a range of compounds, including poorly soluble orhighly soluble drugs. OROS® technology can be used to deliver high drugdoses meeting high drug loading requirements. By targeting specificareas of the gastrointestinal tract, OROS® technology may provide moreefficient drug absorption and enhanced bioavailability. The osmoticdriving force of OROS® and protection of the drug until the time ofrelease eliminate the variability of drug absorption and metabolismoften caused by gastric pH and motility.

Formulations for continuous long-term delivery are provided in, e.g.,U.S. Pat. Nos. 6,797,283; 6,764, 697; 6,635,268, and 6,648,083.

If desired, the components may be provided in a kit. The kit canadditionally include instructions for using the kit.

Additional Methods for Making Modified Release Formulations

Additional methods for making modified release formulations aredescribed in, e.g., U.S. Pat. Nos. 5,422,123, 5,601,845, 5,912,013, and6,194,000, all of which are hereby incorporated by reference.

In some embodiments, for example, the composition may be delivered viaintranasal, buccal, or sublingual routes to the brain rather than byinhalation to enable transfer of the active agents through the olfactorypassages into the CNS and reducing the systemic administration. Devicescommonly used for this route of administration are included in U.S. Pat.No. 6,715,485. Compositions delivered via this route may enableincreased CNS dosing or reduced total body burden reducing systemictoxicity risks associated with certain drugs.

Preparation of a pharmaceutical composition for delivery in asubdermally implantable device can be performed using methods known inthe art, such as those described in, e.g., U.S. Pat. Nos. 3,992,518;5,660,848; and 5,756,115.

The invention will be illustrated in the following non-limitingexamples.

EXAMPLES Example 1 Measuring Release Profiles In Vitro

Compositions containing an aminoadamantane and levodopa/carbidopa areanalyzed for release of the aminoadamantane and levodopa/carbidopa,according to the USP type 2 apparatus at a speed of 50 rpm. Thedissolution media used include water, 0.1N HCl, or 0.1N HCl adjusted topH 6.8 at 2 hours with phosphate buffer. The dissolution medium isequilibrated to 37±0.5° C.

The USP reference assay method for amantadine is used to measure thefraction of memantine released from the compositions prepared herein.Briefly, 0.6 mL sample (from the dissolution apparatus at a given timepoint) is placed into a 15 mL culture tube. 1.6 mL 0.1% BromocresolPurple (in acetic acid) is added and vortexed for five seconds. Themixture is allowed to stand for approximately five minutes. 3 mLChloroform is added and vortexed for five seconds. The solution is nextcentrifuged (speed 50 rpm) for five minutes. The top layer is removedwith a disposable pipette. A sample is drawn into 1 cm flow cell and theabsorbance is measured at 408 nm at 37° C. and compared against astandard curve prepared with known quantities of the sameaminoadamantane. The quantity of determined is plotted against thedissolution time for the sample.

The USP reference assay method for levodopa is used to measure thefraction of levodopa released from the compositions prepared herein.Briefly, 0.5 ml samples from the dissolution apparatus removed atvarious times are assayed by liquid chromatography. The chromatograph isequipped with a 280 nm detector and a 3.9 mm×30 cm column containingpacking L1. The mobile phase is 0.09 N sodium phosphate, 1 mM sodium1-decanesulfonate, pH 2.8. With the flow rate adjusted to about 2 mL perminute, the levodopa elutes in about 4 minutes and carbidopa elutes inabout 11 minutes. From the saved dissolution samples, a 0.02 ml aliquotis injected into the chromatograph and the absorbance is measure andcompared to standard to determine concentration & quantity. The quantitydissolved is then plotted against the dissolution time for the sample.

Example 2 Preparation of Amantadine Extended Release Capsules

Amantadine extended release capsules may be formulated as follows or asdescribed, for example, in U.S. Pat. No. 5,395,626.

A. Composition: Unit Dose

The theoretical quantitative composition (per unit dose) for amantadineextended release capsules is provided below.

Component % weight/weight mg/Capsule Amantadine 68.34 200.00 OPADRY ®Clear YS-3-7011 ¹ 1.14 5.01 (Colorcon, Westpoint, PA) Purified Water,USP ² — — Sugar Spheres, NF 12.50 54.87 OPADRY ® Clear YS-1-7006 ³ 4.4819.66 (Colorcon, Westpoint, PA) SURELEASE ® E-7-7050 ⁴ 13.54 59.44(Colorcon, Westpoint, PA) Capsules ⁵ — — TOTAL. 100.00% 338.98 mg⁶ ¹ Amixture of hydroxypropyl methylcellulose, polyethylene glycol, propyleneglycol. ² Purified Water, USP is evaporated during processing. ³ Amixture of hydroxypropyl methylcellulose and polyethylene glycol ⁴ Solidcontent only of a 25% aqueous dispersion of a mixture of ethylcellulose, dibutyl sebacate, oleic acid, ammoniated water and fumedsilica. The water in the dispersion is evaporated during processing. ⁵White, opaque, hard gelatin capsule, size 00. ⁶ Each batch is assayedprior to filling and the capsule weight is adjusted as required toattain 200 mg amantadine per capsule.

The quantitative batch composition for amantadine extended releasecapsule is shown below. (Theoretical batch quantity 25,741 capsules).

Step 1: Prep of Amantadine HC1 Beads (bead Build-up #1) Component Weight(kg) Amantadine 12.000 OPADRY ® Clear YS-3-7011 0.200 Purified Water,USP 5.454 Sugar Sphere, NF 4.000 Total Weight Amantadine 16.200 kg Beads

The amantadine beads obtained from step 1 are used as follows.

Step 2: Clear & Sustained Release Bead Coating #1 Component Weight (kg)Amantadine Beads 8.000 OPADRY ® Clear YS-1-7006 0.360 Purified Water,USP 5.928 Surelease ® E-7-7050 0.672 Total Weight Clear Coated 9.032 kgSustained Release Beads

The sustained release beads obtained from step 2 are used as follows.

Step 3: Amantadine HC1 Beads (Build-up #2) Component Weight (kg)Sustained Release Beads 8.000 Amantadine 4.320 OPADRY ® Clear YS-3-70110.072 Purified Water, USP 1.964 Total Weight Amantadine 12.392 kg Beads

The amantadine beads obtained from step 3 are formulated as follows.

Step 4: Clear & Sustained Release Bead Coating #2 Component Weight (kg)Amantadine Beads 10.000 OPADRY ® Clear YS-1-7006 0.250 Purified Water,USP 6.450 Surelease ® E-7-7050 1.050 Total Weight Amantadine 11.300 kgExtended Release Beads Step 5: Capsule Filling—Gelatin capsules, size00, are filled with 339 mg of the amantadine beads prepared in step 4.

Example 3 Extended Release Amantadine Formulation with Immediate ReleaseCarbidopa and Levodopa

Levodopa and Carbidopa are formulated into pellets suitable for filling,yet having an immediate release profile. (see, for example, U.S. Pat.No. 5,912,013).

Levodopa plus Carbidopa Core Pellets Weight Percent Kilograms MCC 25.00.25 Hydroxypropylmethylcellulose 10.0 0.10 Phthalate (HPMCP) TartaricAcid 10.0 0.10 Sodium Monoglycerate 7.5 0.075 DSS 0.5 0.005 Levodopa35.8 0.358 Carbidopa 11.2 0.112 TOTAL 100.0% 1.00 kg Coating CelluloseAcetate Phthalate 60.0 0.60 (CAP) Ethylcellulose 25.0 0.25 PEG-400 15.00.15 TOTAL 100.0% 1.00 kg

The pellets are assayed for levodopa and carbidopa content. It isdetermined that approximately 223 mg of the pellets contain 80 mglevodopa and 25 mg carbidopa. Dissolution greater than 90% in 30 minutesis also confirmed.

A total of 669 grams of the pellets are blended with 510 grams of theamantadine pellets from Example 2 in a V-blender for 30 minutes at 30rpm. Gelatin capsules are filled with 393 mg of the mixture and theassays for content are repeated verifying a composition of 100 mgamantadine, 80 mg levodopa, and 25 mg carbidopa.

Example 4 Predicted Dissolution and Plasma Profiles of AmantadineControlled Release

Using the formulations described above, the dissolution profiles foramantadine were simulated and used to calculate plasma profilesresulting from single or multiple administrations using thepharmacokinetic software, GastroPlus v.4.0.2, from Simulations Plus (seeFIG. 2). The initial slope of the dissolution for the sustained releaseformulation is less than the slope determined for the immediate releaseformulation (see FIG. 1) and the corresponding serum profile also showsa slower dC/dT (see FIG. 4).

Example 5 Release Profile of Amantadine and L-DOPA (Levodopa/Carbidopa)

Release proportions are shown in the tables below for a combination ofamantadine and levodopa/carbidopa . The cumulative fraction is theamount of drug substance released from the formulation matrix to theserum or gut environment (e.g., U.S. Pat. Nos. 4,839,177 or 5,326,570 )or as measured with a USP II Paddle system using 0.1 N HCl as thedissolution medium.

LEVODOPA/CARBIDOPA AMANTADINE T½ = 15 hrs T½ = 15 hrs Time cum. fractionA Cum. fraction B 0 0.00 0.00 0.5 0.10 0.40 1.0 0.20 0.95 2.0 0.35 1.004.0 0.60 1.00 8.0 0.90 1.00 12.0 0.98 1.00

Example 6 Treating Dyskinesia in Patients with Parkinson's Disease

A Parkinson's patient experiencing dyskinesia is administered thecomposition of Example 3 three times each day to receive 300 mgamantadine, 240 mg levodopa, and 75 mg carbidopa daily. The Parkinsonismis reduced as measured by the UPDRS (Goetz et al., Mov. Disord.19:1020-8, 2004, incorporated by reference) as is the dyskinesia (Vitaleet al., Neurol. Sci. 22:105-6, 2001, incorporated by reference)

Example 7 Animal Models Showing Reduced Dyskinesia, Reduced LevodopaPotential

The following protocol was employed to demonstrate the beneficialeffects of the compositions of this invention. Briefly, squirrel monkeys(N=4) were lesioned with MPTP according to the protocol of Di Monte etal. (Mov. Disord. 15: 459-66 (2000)). After 3 months, the monkeys showedfull symptoms of Parkinson's disease as measured by a modified UPDRS(Goetz et al., Mov. Disord. 19:1020-8, 2004). Levodopa treatment atapproximately 15 mg/kg (with 1.5 mg/kg carbidopa) mg/kg b.i.d. commenceda baseline UPDRS and dyskinesia measurement was established. Amantadinewas added to the regimen simultaneously with the levodopa, and theamount raised from 1 mg/kg to 45 mg/kg for four of the squirrel monkeys,corresponding to an estimated 3 μm concentration. As shown in FIG. 8,the combination led to a 60% reduction in dyskinesia. We hypothesizethat this translates into a potential 40% reduction in levodopa requiredto maintain UPDRS.

Example 8 Levodopa Sparing Therapy

The following protocol is employed to determine the optimal reduction oflevodopa achieved with the addition of Amantadine to a fixed dosecombination product.

Parkinson's DISEASE PROTOCOL SUMMARY NPI MEMANTINE CR MONOTHERAPYProtocol Number: NPI-Amantadine CR Study Phase: 2/3 Name of Drug:NPI-Amantadine/C/L Dosage: 25/100/100 c/l/a given t.i.d. 25/80/100 c/l/agiven t.i.d. 25/60/100 c/l/a given t.i.d. Concurrent Control: 25/100 c/lgiven t.i.d. Route: Oral Subject Population: Male and female patientsdiagnosed with Parkinson's Disease Hoehn and Yahr score of 2-4Structure: Parallel-group, three-arm study Study Term Two weeks StudySites: Multi-center 10 centers Blinding: Double blind Method of SubjectRandomized to one of three treatment groups Assignment: (3:1) TotalSample Size: 320 subjects (160 men, 160 women) Primary Efficacy UPDRSEndpoints: Abnormal involuntary movement scale (AIMS) 0-4 SecondaryEndpoints: Modified Obeso dyskinesia rating scale 0-4 Mini-mental stateexamination (MMSE); Neuropsychiatric Inventory Score (NPI) AdverseEvents: Monitored and elicited by clinic personnel throughout the study,volunteered by patients

Example 9 Pharmaceutical Composition Including Memantine, Levodopa, andCarbidopa

A co-formulation of memantine, levodopa and carbidopa is prepared. Thisco-formulation matches the absorption properties of levodopa andcarbidopa more closely than those of Memantine, thereby extending theeffectiveness per dose of levodopa and carbidopa. The co-formulationprovides Tmax values to about 4 hours and allows b.i.d. dosing of thecombination.

FIG. 6 provides the current single oral dose pharmacokinetic (PK)profiles for levodopa, carbidopa and memantine. FIG. 7 providesidealized pharmacokinetic profiles for the target co-formulation, inwhich the Tmax values for levodopa and carbidopa more closely match thatof Memantine.

Dosage Form: Tablet Formulation Levodopa 150 mg Content: Carbidopa 37.5mg Memantine 10 mg Excipients: FDA approved excipients and drug releasemodifiers. Additional embodiments are within the claims.

Example 10 Pharmaceutical Composition Including Extended ReleaseFormulations of Memantine and Levodopa

A pulsatile release dosage form for administration of memantine andlevodopa may be prepared as three individual compartments. Threeindividual tablets are compressed, each having a different releaseprofile, followed by encapsulation into a gelatin capsule, which arethen closed and sealed. The components of the three tablets are asfollows.

Amount Component Function per tablet TABLET 1 (IMMEDIATE RELEASE):Memantine Active agent 8 mg Levodopa Active agent 70 mg Dicalciumphosphate dihydrate Diluent 26.6 mg Microcrystalline cellulose Diluent26.6 mg Sodium starch glycolate Disintegrant 1.2 mg Magnesium StearateLubricant 0.6 mg TABLET 2 (RELEASE DELAYED 3-5 HOURS FOLLOWINGADMINISTRATION): Memantine Active agent 8 mg Levodopa Active agent 70 mgDicalcium phosphate dihydrate Diluent 26.6 mg Microcrystalline celluloseDiluent 26.6 mg Sodium starch glycolate Disintegrant 1.2 mg MagnesiumStearate Lubricant 0.6 mg Eudragit RS3OD Delayed release 4.76 mg coatingmaterial Talc Coating component 3.3 mg Triethyl citrate Coatingcomponent 0.95 mg TABLET 3 (RELEASE DELAYED 7-9 HOURS FOLLOWINGADMINISTRATION): Memantine Active agent 2.5 mg Levodopa Active agent 70mg Dicalcium phosphate dihydrate Diluent 26.6 mg Microcrystallinecellulose Diluent 26.6 mg Sodium starch glycolate Disintegrant 1.2 mgMagnesium Stearate Lubricant 0.6 mg Eudragit RS3OD Delayed release 6.34mg coating material Talc Coating component 4.4 mg Triethyl citrateCoating component 1.27 mg

The tablets are prepared by wet granulation of the individual drugparticles and other core components as may be done using a fluid-bedgranulator, or are prepared by direct compression of the admixture ofcomponents. Tablet 1 is an immediate release dosage form, releasing theactive agents within 1-2 hours following administration. Tablets 2 and 3are coated with the delayed release coating material as may be carriedout using conventional coating techniques such as spray-coating or thelike. As will be appreciated by those skilled in the art, the specificcomponents listed in the above tables may be replaced with otherfunctionally equivalent components, e.g., diluents, binders, lubricants,fillers, coatings, and the like.

Oral administration of the capsule to a patient will result in a releaseprofile having three pulses, with initial release of the memantine andlevodopa from the first tablet being substantially immediate, release ofthe memantine and levodopa from the second tablet occurring 3-5 hoursfollowing administration, and release of the memantine and levodopa fromthe third tablet occurring 7-9 hours following administration.

Example 11 Pharmaceutical Composition Including Extended ReleaseFormulations of Memantine, Levodopa, and Carbidopa

The method of Example 9 is repeated, except that drug-containing beadsare used in place of tablets. Carbidopa is also added in each of thefractions at 25% of the mass of the levodopa. A first fraction of beadsis prepared by coating an inert support material such as lactose withthe drug which provides the first (immediate release) pulse. A secondfraction of beads is prepared by coating immediate release beads with anamount of enteric coating material sufficient to provide a drugrelease-free period of 3-5 hours. A third fraction of beads is preparedby coating immediate release beads having half the methylphenidate doseof the first fraction of beads with a greater amount of enteric coatingmaterial, sufficient to provide a drug release-free period of 7-19hours. The three groups of beads may be encapsulated or compressed, inthe presence of a cushioning agent, into a single pulsatile releasetablet.

Alternatively, three groups of drug particles may be provided and coatedas above, in lieu of the drug-coated lactose beads.

Other Embodiments

While the invention has been described in conjunction with the detaileddescription thereof, the foregoing description is intended to illustrateand not limit the scope of the invention, which is defined by the scopeof the appended claims. Other aspects, advantages, and modifications arewithin the scope of the following claims.

What is claimed is: 1.-11. (canceled)
 12. A method of treatingdyskinesia, comprising: orally administering, once-daily to a humansubject with Parkinson's disease who is taking levodopa, apharmaceutical composition comprising 50 mg to 500 mg of a drug selectedfrom the group consisting of amantadine and pharmaceutically acceptablesalts thereof in an extended release dosage form, said extended releasedosage form comprising a capsule containing coated pellets; wherein saidcoated pellets comprise 1) drug-containing pellets having an inert corecovered with amantadine or a pharmaceutically acceptable salt thereofand a binder, and 2) a release-modifying coating layer on saiddrug-containing pellets, said release-modifying coating layer comprises(i) a water insoluble polymer, (ii) 15% to 85% by weight of a watersoluble pore forming material, and (iii) 0% to 50% by weight of aplasticizer, and said pharmaceutical composition having an in vitrodissolution profile ranging between 0% and 20% in 1 hour, 70% or greaterin 10 hours, and 90% or greater in 12 hours, using a USP type 2 (paddle)dissolution system at 50 rpm at a temperature of 37±0.5° C. in water.13. The method of claim 12, wherein said pharmaceutical composition hasan in vitro dissolution profile in water of less than 10% in 30 minutesand more than 95% in 16 hours as determined using a USP type II (paddle)dissolution system at 50 rpm at a temperature of 37±0.5° C.
 14. Themethod of claim 12, wherein 200 mg to 500 mg of amantadine or apharmaceutically acceptable salt is administered daily to said humansubject.
 15. The method of claim 12, wherein said method reduces thefrequency or severity of dyskinesia.
 16. The method of claim 12, whereinsaid extended release dosage form provides a shift in amantadine Tmax of2 hours to 16 hours relative to the Tmax of an immediate release form ofamantadine when the Tmax of said extended release dosage form and theimmediate release form are determined in a single dose humanpharmacokinetic study.
 17. The method of claim 12, wherein said extendedrelease dosage form provides a shift in amantadine Tmax of 4 hours to 16hours relative to the Tmax of an immediate release form of amantadinewhen the Tmax of said extended release dosage form and the immediaterelease form are determined in a single dose human pharmacokineticstudy.
 18. The method of claim 12, wherein said extended release dosageform provides a Tmax of 5 to 19 hours.
 19. The method of claim 12,wherein said extended release dosage form provides a Tmax of 7 to 19hours.
 20. The method of claim 12, wherein said inert core is a sugarsphere, NF.
 21. The method of claim 12, wherein said binder compriseshydroxypropyl methylcellulose.
 22. The method of claim 12, wherein saidwater insoluble polymer comprises ethyl cellulose.
 23. The method ofclaim 12, wherein said water soluble pore forming material compriseshydroxypropyl methyl cellulose.
 24. The method of claim 12, wherein saidwater soluble pore forming material comprises polyvinylpyrrolidone. 25.The method of claim 12, wherein said composition is administered oncedaily in multiple dosage forms.
 26. The method of claim 12, wherein saidcomposition is encapsulated.